DESCRIPTION (Adapted from abstract): The molecular basis of muscle force is a configurational change in the myosin head while attached to actin. Such a change could either be a conformational change within the head itself, or it may be an alteration in the binding angle made with actin. The energy for force production is known to come from ATP hydrolysis, but while the "tilting cross-bridge" hypothesis remains attractive, it is still unproven. Moreover, recent structural data have suggested that the configuration of attached myosin heads may be similar in both the ATP and ADP-Pi states. One problem in testing the tilting bridge hypothesis has been the difficulty of establishing the structures of so-called weakly bound acto-myosin states that occur in the presence of ATP. A considerable amount is known about the structure of the strongly bound states that occur in ADP or no nucleotide. However, other bound states have been elusive either because they dissociate at the low protein concentrations required for moderate resolution microscopy of the acto-myosin head (S1) complex or they are present only transiently. The applicant recently found conditions that allow one to observe transient and weakly bound states and has been studying their structures by electron cryo-microscopy of hydrated specimens. The micrographs already obtained show a variety of attached S1 configurations during steady-state ATP hydrolysis; such data are therefore compatible with the tilting bridge hypothesis but do not prove it.